Sex-steroid milieu determines diabetes rescue in pttg-null mice

Abstract

Male mice that are pttg -null develop sexually dimorphic diabetes with hypoinsulinemia secondary to reduced post-natal -cell proliferation and an inability to expand islet cell mass with aging. We therefore examined the effects of sex-steroid manipulation on diabetes development in pttg −/− male mice. Surgical gonadectomy was followed by implantation of 90-day slow-release pellets releasing 17β-estradiol (0.36 mg/pellet), placebo or dihydrotestosterone (DHT; 12.5 mg/pellet). Mean fasting blood sugars at the end of the study were 414 ± 54 mg/dl for pttg −/− controls and 371 ± 14 mg/dl for pttg −/− mice gonad-ectomized and treated with DHT compared with 124 ± 40 and 85 ± 12 mg/dl in gonadectomized pttg −/− males treated with placebo or estradiol, respectively ( P < 0.01 compared with control pttg −/− ). Gonadectomy with and without estradiol treatment did not increase the very low circulating insulin levels in pttg -null males (fasting insulin 0.44 ± 0.04 ng/ml in pttg −/− controls, 0.47 ± 0.07 and 0.4 ng/ml in pttg −/− gonadectomized males treated with placebo or estradiol, respectively). Gonadectomy increased serum adiponectin levels (4.9 ± 008 μg/ml in pttg −/− controls versus 13 ± 0.08 and 7.5 ± 0.6 μg/ml in pttg −/− gonadectomized males treated with placebo or estradiol, respectively; P < 0.001 and P < 0.05), accompanied by increased insulin sensitivity. The results show that gonadectomy delayed, and gonadectomy with additional estradiol treatment prevented, diabetes development in pttg −/− males, possibly through increased insulin sensitivity mediated by elevated serum adiponectin levels. Male-selective effects of disrupted β-cell proliferation in the absence of pttg are restored by sex-steroid effects on peripheral insulin sensitivity.